This invention relates to a chemical synthetic process and will have application to a process for synthesizing disulfide compounds and intermediates thereof.
Mesna (sodium 2-mercaptoethane sulfonate; Mesnex®; Uromitexan®) and dimesna (disodium 2,2′-dithiobis ethane sulfonate; BNP7787; Tavocept™) are known therapeutic compounds that have heretofore demonstrated a wide variety of therapeutic uses. Both mesna and dimesna have been shown to be effective protective agents against certain specific types of toxicity associated with the administration of cytotoxic drugs used to treat patients for various types of cancer.
In particular, mesna is an approved agent in most major markets, and has been used with some success in mitigating the toxic effects of cytotoxic agents such as ifosfamide, oxazaphosphorine, melphalane, cyclophosphamide, trofosfamide, sulfosfamide, chlorambucil, busulfan, triethylene thiophosphamide, triaziquone, and others, as disclosed in U.S. Pat. No. 4,220,660, issued Sep. 2, 1980.
Dimesna is in late stage human clinical trials in most major pharmaceutical markets, and has exhibited efficacy in mitigating the undesired toxic effects of various platinum antineoplastic agents, as well as the neurotoxic effects of paclitaxel.
Further, pharmacological profiles of each compound indicate that, if proper conditions are maintained, mesna and dimesna do not prematurely inactivate primary therapeutic drugs to a significant degree. Thus, neither compound is likely to significantly reduce activity of the chemotherapeutic agent, and in many cases, dimesna has been observed to potentiate the effect of the main drug on targeted cancer cells.
The structures of both mesna and dimesna are shown below:

As is well known, dimesna is an oxidative dimer of mesna. In the slightly basic (pH˜7.3), oxygen rich environment found in blood plasma, dimesna is present in large part in its oxidized form. In mildly acidic, low oxygen conditions, in the presence of a reducing agent such as glutathione reductase, conditions prevalent in the kidneys, dimesna is reduced to mesna.
Mesna acts as a protective agent for a number of cytotoxic agents by converting a toxic metabolite of the cytotoxic agent (acrolein in the case of ifosfamide) to a relatively harmless compound in vivo. This action is particularly evidenced in the coadministration of mesna and an oxazaphosphorine. Dimesna acts as a protective agent by converting a toxic hydroxy or aquo moiety of the active agent to a relatively harmless mercaptan, particularly in the administration of dimesna along with a platinum agent.
Mesna and dimesna, as well as some analogues of these compounds, have excellent toxicity profiles in mammalian species. Dimesna has been administered intravenously to mice and dogs in doses higher than the accepted oral LD50 for common table salt (3750 mg/kg), with no adverse effects.
Mesna, and other analogues with free thiol moieties, constitute the more physiologically active form of the two types of compounds described in this specification. These compounds manifest their activity by providing free thiol moieties for terminal substitution at locations where a terminal leaving group of appropriate configuration is located.
Dimesna and other disulfides can be activated intracellularly by glutathione reductase, a ubiquitous enzyme, thereby generating high concentrations of intracellular free thiols. These free thiols act to scavenge the free radicals and other nucleophilic compounds often responsible for causing cell damage.
This profile is especially significant in explaining the success of dimesna in controlling and mitigating the toxic effects of platinum complex antitumor drugs. The mechanism for action in the case of cisplatin (cis-diammine dichloro platinum) is explained in U.S. Pat. No. 5,789,000, the disclosure of which is incorporated herein by reference.
Mesna, dimesna, and analogues of these compounds have been the subject of several prior pharmaceutical uses described in the literature and in prior patents, both in the United States and around the world.
Mesna, dimesna, and analogues thereof have been previously synthesized from commonly available starting materials, using acceptable routes well known in the art. See, for example, U.S. Pat. No. 5,808,140. One such method involves the two-step, single pot synthetic process for making dimesna, and other sulfur-containing alkali metal compounds of the following Formula I:R1—S—R2;  (I)
wherein:                R1 is hydrogen, —X-lower alkyl or —X-lower alkyl-R3;        R2 is -lower alkyl-R4;        R3 and R4 are each individually —SO3M or —PO3M2;        X is absent or is sulfur; and        M is an alkali metal.        
The prior process involves a two-step single pot synthetic process, which results in the conversion of an alkenyl sulfonate salt or acid to the desired Formula I compound. The process in the case of mesna is a single step process that converts the alkenyl sulfonate salt to mesna or a mesna derivative by reacting with an alkali metal sulfide or with hydrogen sulfide.
If the desired end product is dimesna or a dimesna analogue, a two-step single pot process is involved. Step 1 is as described above. Step 2 of the process is performed in the same reaction vessel as Step 1 without the need to purify or isolate the mesna formed during that step. Step 2 includes the introduction of oxygen gas into the vessel, along with an increase in pressure and temperature above ambient values, at least 20 pounds per square inch (psi) and at least 60° C. Dimesna or a derivative thereof is formed in essentially quantitative yield.
Hitherto, it is known that disodium 2,2′-dithiobis ethane sulfonate is produced, for example, by oxidizing sodium 2-mercaptoethane sulfonate, which is obtained by addition to sodium vinyl sulfonate, with oxygen at 60° C. However, this process has a problem, in that it produces a by-product, disodium 2,2′-monothiobis ethane sulfonate, that is difficult to remove.
A method is also known for producing disodium 2,2′-dithiobis ethane sulfonate which comprises allowing sodium 2-bromoethane sulfonate to react with sodium thioacetate, neutralizing the product to give sodium 2-mercaptoethane sulfonate and oxidizing it with oxygen to afford disodium 2,2′-dithiobis ethane sulfonate (U.S. Published Patent Application Publication No. US 2004/0024346 A1, published Feb. 5, 2004). In this method, several unknown by-products are formed at 50–60° C., recommended as the oxidizing temperature, and it is difficult to remove them. Further, solids tend to be produced while drying, because the solvent for crystallizing is a mixture of ethanol with water.
The raw material, sodium 2-bromoethane sulfonate, is known to be prepared by allowing a 1:1.9 mixture of isethionic acid with sodium isethionate to react with hydrobromic acid, cooling the product to give crystals and recrystallizing from 96% ethanol (German Democratic Republic Patent No. DD 154,815). However, isethionic acid is expensive.
Therefore, there is a need for and it is desired to establish a method for producing disodium 2,2′-dithiobis ethane sulfonate from available raw compounds in good yield with high purity. The present invention satisfies this need.